Cardiovascular complications caused by atherosclerosis are the major cause of death in patients with type 1 diabetes. While searching for a mechanism of diabetes-accelerated atherosclerosis in a mouse model of type1diabetes, we discovered that the pro-inflammatory protein S100A9 is secreted at increased levels from macrophages from diabetic mice, and that immunoreactive S100A9 is abundant in atherosclerotic lesions from diabetic mice and correlates with intraplaque hemorrhage. Interestingly, recent studies identify S100A9 and its binding partner S100A8 as biomarkers of cardiovascular events in humans. Monocytes isolated from humans with type 1 diabetes express high levels of S100A9, raising the possibility that S100A8/A9 plays an important role in diabetic vascular disease. Based on these observations and preliminary studies, we hypothesize that type 1 diabetes promotes an inflammatory population of macrophages in tissues, and that this population secretes elevated levels of S100A8/A9. We further hypothesize that S100A8/A9 promotes atherosclerosis in type 1 diabetes by two mechanisms: i) regulation of macrophage activation state; and ii) local inflammatory effects in the artery wall. The proposed experiments will be carried out in isolated mouse macrophages, in an S100A9-deficient mouse, and in a transgenic LDL receptor-deficient mouse model of atherosclerosis in which type 1 diabetes can be induced by a virus (the LDLR-/-;GP mouse). We propose to directly test the contribution of S100A8/A9 in inflammation and diabetes-accelerated atherosclerosis. The goal is to address the following three questions: 1) Does type 1 diabetes promote accumulation of inflammatory macrophages in tissues? 2) Does S100A8/A9 regulate macrophage activation in type 1 diabetes? 3) Does S100A8/A9 promote lesion initiation and/or progression in type 1 diabetes?